1. Field of the Invention
This invention relates to a controlled absorption pharmaceutical formulation and, in particular, to a controlled absorption form of diltiazem for oral administration.
2. Description of the Prior Art
Diltiazem-cis-(+)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4 -methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia while displaying a low incidence of side effects. Diltiazem is conventionally administered in normal capsule form as diltiazem hydrochloride sold under the Trade Mark Cardiazem (Marion Laboratories Inc.).
Conventional diltiazem therapy starts with 30 mg administered 4 times daily. The dosage is gradually increased to 240 mg, given in divided doses three or four times daily, at one- to two-day intervals until an optimum response is obtained. Diltiazem is extensively metabolized by the liver and excreted by the kidneys and in bile. According to professional use information issued by Marion Laboratories Inc., diltiazem is absorbed from the known tablet formulation (Cardiazem) to about 80% and is subject to an extensive first-pass effect, giving an absolute bioavailability, compared to intravenous administration, of about 40%. Single oral doses of 30 to 120 mg of diltiazem result in peak plasma levels 2-3 hours after administration. Detectable plasma levels occur within 30-60 minutes after administration indicating that diltiazem is readily absorbed.
The plasma elimination half-life following single or multiple administration is approximately 3-5 hours. Therapeutic blood levels of diltiazem are thought to be in the range of 50-200 ng/ml.
An article by McAuley, Bruce. J. and Schroeder, John S. in Pharmacotherapy 2: 121, 1982, states that peak plasma levels of diltiazem occur within 1 hour with normal capsules and within 3 to 4 hours with sustained release tablets.
It is an object of the present invention to provide a controlled absorption diltiazem formulation suitable for twice daily administration and which has improved bioavailability relative to known diltiazem oral formulations.